Publicaciones

Mitochondrial sodium/calcium exchanger NCLX regulates glycolysis in astrocytes, impacting on cognitive performance

Cabral-Costa JV, Vicente-Gutiérrez C, Agulla J, Lapresa R, Elrod JW, Almeida Á, Bolaños JP, Kowaltowski AJ. J Neurochem. 2022 Dec 23. doi: 10.1111/jnc.15745. Online ahead of print. PMID: 36563047
Abstract: Intracellular Ca2+ concentrations are strictly controlled by plasma membrane transporters, the endoplasmic reticulum, and mitochondria, in which Ca2+ uptake is mediated by the mito c ho nd r ia l c a lc ium unip o rte r c o mp le x (M C Uc ), while e fflu x occurs ma in ly through the mito c ho nd r ia l Na+/Ca2+ exchanger (N C LX). RNAseq database repository searches led us to identify the Nclx transcript as highly enriched in astrocytes when compared to neurons. To assess the role of NCLX in mo us e p rima ry c ulture astrocytes, we inhib ited its functio n both pharmacologically or genetically. This re s ulte d in re -shaping of c yto s o lic C a2+ signa ling and a me ta b o lic s hift that increased glycolyt ic flux and lactate secretion in a C a2+-dependent manner. Interestingly, in v iv o genetic deletion of N CLX in hippocampal astrocytes improved cognit ive performance in behavioral tasks, whereas hippocampal neuron-specific deletion of NCLX imp a ire d cognitive performance. These results unveil a role for N CLX as a novel modulator of astrocytic glucose metabolism, impacting on cognition.
Funding: Authors were supported by grant #2020/06970–5 from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP); Centro de Pesquisa, Inovação e Difusão de Processos Redox em Biomedicina (CEPID Redoxoma, FAPESP grant #2013/07937–8); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) line 001; Agencia Estatal de Investigación (PID2019-105699RB-I00/AEI/10.13039/501100011033, PDC2021-121013-I00 and RED2018‐102576‐T to JPB); Plan Nacional de Drogas (2020I028 to JPB); Instituto de Salud Carlos III (PI21/00727 and RD21/0006/0005 co-funded by the European Union FEDER/FSE+ and NextGenerationEU to AA); and Junta de Castilla y León(CS/151P20 co-funded by P.O. FEDER to AA; Apoyo Regional a la Competitividad Empresarial, ICE 04/18/LE/0017 to JPB, and Escalera de Excelencia CLU-2017-03 to JPB and AA). JVCC was also supported by FAPESP fellowships #2017/14713-0 and #2019/22178-2.

Association of blood-based biomarkers with radiologic markers and cognitive decline in atrial fibrillation patients

Palà E, Escudero-Martínez I, Penalba A, Bustamante A, Lamana-Vallverdú M et al. J Stroke Cerebrovasc Dis. 2022 Dec;31(12):106833. doi: 10.1016/j.jstrokecerebrovasdis.2022.106833. Epub 2022 Oct 26.PMID: 36309005
Background: Atrial fibrillation (AF) has been associated with an increased risk of silent brain infarcts (SBI) and cognitive impairment, even in patients with low embolic risk. We aimed to test the association between 11 blood-biomarkers representing different AF-related pathways, and SBI, white matter hyperintensities (WMH), and cognitive decline in patients with AF and low embolic risk. Methods: The present study followed a cross-sectional design. 70 patients with a history of AF and CHADS2 score 1, and 10 controls with neither AF nor SBI were included. All patients underwent a 3T brain
MRI. Cortical and large subcortical ischemic lesions were considered presumed embolic origin lesions. White matter hyperintensities (WMH) were measured according to the Fazekas scale. A subset of patients underwent cognitive evaluation with the MoCA test. Circulating proteins were measured under blind conditions in a laboratory at Roche Diagnostics, Germany. Results: 45 patients presented SBI in the MRI, and 25 did not. Ang-2, FGF-23, and BMP-10 were increased in patients with SBI. Ang-2 was elevated only in patients with embolic infarcts, whereas FGF-23 and BMP-10 tended to
be elevated in patients with both types of infarcts. Ang-2 (OR = 1.56 [0.94-2.59], p = 0.087), and BMP-10 (OR = 4.83 [0.9923.60], p = 0.052) were the biomarkers that showed the highest association with SBI when entered in a multivariable logistic regression model corrected by age. No biomarker was found associated with WMH or mild cognitive impairment. Conclusions: BMP-10, and Ang-2 were increased in patients with SBI. Its usefulness to detect SBI in AF patients should be further explored.
Funding: A Junta de Andalucía grant (PIN-0144-2016) supported partially the study. The Fundacion Cajasol contributed to the study. Neurovascular Research Groups at Seville and Barcelona are part of the Spanish Neurovascular Disease Research Network (RICORS-ICTUS, RD21/0006/0007).

Improving the Efficacy of Quinolylnitrones for Ischemic Stroke Therapy, QN4 and QN15 as New Neuroprotective Agents after Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury

Alonso JM, Escobar-Peso A, Fernández I, Alcázar A, Marco-Contelles J. Pharmaceuticals (Basel). 2022 Nov 7;15(11):1363. doi: 10.3390/ph15111363.PMID: 36355534
Abstract: In our search for new neuroprotective agents for stroke therapy to improve the pharmacological profile of the compound quinolylnitrone QN23, we have prepared and studied sixteen new, related and easily available quinolylnitrones. As a result, we have identified compounds QN4 and QN15 as promising candidates showing high neuroprotection power in a cellular experimental model of ischemia. Even though they were found to be less active than our current lead compound QN23, QN4 and QN15 provide an improved potency and, particularly for QN4, an expanded range of tolerability and improved solubility compared to the parent compound. A computational DFT-based
analysis has been carried out to understand the antioxidant power of quinolylnitrones QN23, QN4 and QN15. Altogether, these results show that subtle, simple modifications of the quinolylnitrone scaffold are tolerated, providing high neuroprotective activity and optimization of the pharmacological potency required for an improved design and future drug developments in the field.
Funding: This work was supported by Instituto de Salud Carlos III and cofinanced by the European Regional Development Fund (FEDER), grant number PI18/0255 and RETICS RD21/0006/0019, to A.A, and by MINECO (Government of Spain) grant number SAF-2015-65586-R to J.M.-C

Bioevaluation of magnetic mesoporous silica rods: cytotoxicity, cell uptake and biodistribution in zebrafish and rodents

Grzelak J, Teles M, Roher N, Grayston A, Rosell A, Gich M, Roig A. RSC Adv. 2022 Nov 7;12(49):31878-31888. doi: 10.1039/d2ra05750f. eCollection 2022 Nov 3.PMID: 36380961
Mesoporous silica nanoparticles (MSN) characterized by large surface area, pore volume, tunable chemistry, and biocompatibility have been widely studied in nanomedicine as imaging and therapeutic carriers. Most of these studies focused on spherical particles. In contrast, mesoporous silica rods (MSR) that are more challenging to prepare have been less investigated in terms of toxicity, cellular uptake, or biodistribution. Interestingly, previous studies showed that silica rods penetrate fibrous tissues or mucus layers more efficiently than their spherical counterparts. Recently, we reported the synthesis of MSR with distinct aspect ratios and validated their use in multiple imaging modalities by loading the pores with maghemite nanocrystals and functionalizing the silica surface with green and red fluorophores. Herein, based on an initial hypothesis of high liver accumulation of the MSR and a future vision that they could be used for early diagnosis or therapy in fibrotic liver diseases; the cytotoxicity and cellular uptake of MSR were assessed in zebrafish liver (ZFL) cells and the in vivo safety and biodistribution was investigated via fluorescence molecular imaging (FMI) and magnetic resonance imaging (MRI) employing zebrafish larvae and rodents. The selection of these animal models was prompted by the well-established fatty diet protocols inducing fibrotic liver in zebrafish or rodents that serve to investigate highly prevalent liver conditions such as non-alcoholic fatty liver disease (NAFLD). Our study demonstrated that magnetic MSR do not cause cytotoxicity in ZFL cells regardless of the rods’ length and surface charge (for concentrations up to 50 mg ml−1 , 6 h) and that MSR are taken up by the ZFL cells in large amounts despite their length of ∼1 mm. In zebrafish larvae, it was observed that they could be safely exposed to high MSR concentrations (up to 1 mg ml−1 for 96 h) and that the rods pass through the liver without causing toxicity. The high accumulation of MSR in rodents’ livers at short post-injection times (20% of the administered dose) was confirmed by both FMI and MRI, highlighting the utility of the MSR for liver imaging by both techniques. Our results could open new avenues for the use of rod-shaped silica particles in the diagnosis of pathological liver conditions.
Acknowledgements: The authors acknowledge nancial support from the Spanish Ministry of Science and Innovation through the PID2021-122645OB-100 project, the ‘Severo Ochoa’ Programme for Centers of Excellence in R&D (CEX2019-000917-S). The Generalitat de Catalunya, projects 2017SGR765 and 2017SGR1427, are also acknowledged. The authors participate in the Aerogels COST ACTION (CA 18125). J. G. has received nancial support through the “la Caixa” INPhINIT Fellowship Grant for Doctoral Studies at Spanish Research Centers of Excellence (grant code: LCF/BQ/DI17/11620041), “la Caixa” Banking Foundation (ID100010434), Barcelona, Spain. J. G. was enrolled in the doctoral program in Materials Science at the UAB. M. T. (ref. RYC2019-026841-I) has a post-doctoral fellowship “Ram´on y Cajal” supported by the “Ministerio de Ciencia e Innovaci´on”, Spanish Government. A. G. has been supported by the fellowship from Instituto de Salud Carlos III with FEDER funds (FI17/ 00073). A. Rosell takes part of the RICORS-STROKE network from Instituto de Salud Carlos III with FEDER funds (RD21/ 0006/0007). This research work was performed in the framework of the Nanomedicine CSIC HUB (ref. 202180E048). Dr Daniel Padro is acknowledged for the supervision of MRI in vivo experiments in ReDIB-Molecular and Functional Imaging Facility at CIC BiomaGUNE which were accessible through the Spanish network of Singular Scientic and Technical Infrastructure (ICTS). Authors thanks Dr Fernando Herranz (IQMCSIC) for fruitful discussions.